{"doi":"10.1016/j.jcf.2025.08.014","title":"Neutrophil store-operated Ca2+ entry: A correctable biomarker of cystic fibrosis lung disease progression","abstract":"Rationale People with cystic fibrosis (pwCF) exhibit chronic and hyperactive neutrophilia which results in a progressive loss of lung function. CF neutrophils have elevated store operated Ca 2+ entry (SOCE) relative to healthy non-CF neutrophils, which contributes to persistent neutrophilia. The vast majority of pwCF now take CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI), which effectively increase CFTR function in multiple organs including the lung. However, ETI's impact on neutrophils is poorly understood. Orai1 is a plasma membrane Ca 2+ channel that contributes to SOCE. We have developed a novel peptide (ELD607) that specifically inhibits Orai1, which we evaluated in CF neutrophils. Objectives To characterize Orai1/SOCE in neutrophils from pwCF taking ETI, and to evaluate the impact of SOCE inhibition by ELD607 on pwCF neutrophil Ca 2+ signaling/function. Methods Peripheral blood neutrophils were isolated by negative selection. SOCE was characterized using fluorescent approaches. Protein expression was characterized by proteomics and confocal microscopy. Neutrophil degranulation was measured using a multiplex assay. Measurements and main results Proteomic analysis revealed major global differences between non-CF and pwCF neutrophils, despite use of ETI. Several proteins involved in SOCE, including Orai1, were significantly elevated in pwCF neutrophils. ELD607 dose-dependently inhibited SOCE, leading to reduced neutrophil degranulation. Ca 2+ homeostasis was significantly elevated in pwCF compared to non-CF neutrophils. ELD607-sensitive SOCE inversely correlated with lung function (FEV1pp). Conclusions Our findings highlight SOCE as a novel biomarker of CF lung disease. ELD607 can be used to reduce SOCE and subsequent degranulation in CF neutrophils. We therefore hypothesize that ELD607 may be of benefit in the management of inflammation in pwCF.","journal":"Journal of Cystic Fibrosis","year":2025,"id":542229,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":800111,"name":"Matthew Biggart","orcid":"0000-0002-9301-5695","position":1,"is_corresponding":false},{"id":366794,"name":"Charles D. Bengtson","orcid":"0000-0002-3177-3992","position":2,"is_corresponding":false},{"id":504646,"name":"Maria F. Sassano","orcid":"0000-0003-1243-2962","position":3,"is_corresponding":false},{"id":295745,"name":"Robert Tarran","orcid":"0000-0002-8598-2642","position":4,"is_corresponding":false},{"id":725287,"name":"Joe A. Wrennall","orcid":null,"position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:52:55.809501Z","pmid":"40877083","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}